Urea hydantoin derivatives as formyl peptide modulators

ABSTRACT

The present invention relates to urea hydantoin compounds, processes for preparing them, pharmaceutical compositions containing them, and their use as pharmaceuticals as modulators of the FPR2 receptor, and to methods of treating inflammatory diseases or conditions in a subject in need thereof by administering the compound(s) or pharmaceutical composition to the subject.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication No. 61/932,968, filed Jan. 29, 2014, the entire contents ofwhich is incorporated herein by this specific reference.

FIELD OF THE INVENTION

The present invention relates to urea hydantoin derivatives, processesfor preparing them, pharmaceutical compositions containing them, andtheir use as pharmaceuticals as modulators of the N-formyl peptide 2receptor (FPR2). The invention relates specifically to the use of thesecompounds and their pharmaceutical compositions to treat disordersassociated with FPR2 modulation.

BACKGROUND OF THE INVENTION

The formyl peptide receptor (FPR) family belongs to the seventransmembrane domain G-protein-coupled receptor (GPCR) family. Thisfamily includes 3 members in humans, and one member of this family, FPR2(also known as FPRL-1, ALXA4), is expressed predominantly oninflammatory cells such as monocytes and neutrophils, as well as on Tcells, and has been shown to play a critical role in leukocytetrafficking during inflammation and human pathology (Chiang N, Serhan CN, Dahlen, S, Drazen J M, Hay D W P, Rovati E, Shimizu T, Yokomizo T,Brink, C. The lipoxin receptor ALX: Potent ligand-specific andstereoselective actions in vivo. Pharmacological Reviews 2006; 58:463-519). FPR2 is an exceptionally promiscuous receptor that responds toa menagerie of structurally diverse exogenous and endogenous ligands,including serum amyloid A (SAA), chemokine variant sCK68-1, theneuroprotective peptide humanin, anti-inflammatory eicosanoid lipoxin A4(LXA4) and glucocorticoid-modulated protein annexin A1 (Chiang N, SerhanC N, Dahlen, S, Drazen J M, Hay D W P, Rovati E, Shimizu T, Yokomizo T,Brink, C. The lipoxin receptor ALX: Potent ligand-specific andstereoselective actions in vivo. Pharmacological Reviews 2006; 58:463-519). FPR2 has been shown to transduce anti-inflammatory effects ofarachidonic acid derived lipoxin A4 (LXA4) in many systems, and has beenshown to play a key role in the resolution of inflammation (Dufton N,Perretti M. Therapeutic anti-inflammatory potential of formyl peptidereceptor agonists. Pharamcology & Therapeutics 2010; 127: 175-188). FPR2knockout mice show exaggerated inflammation in disease conditions asexpected by the biological role of the receptor (Dufton N, Hannon R,Brancaleone V, Dalli J, Patel H B, Gray M, D'Aquisto F, Buckingham J C,Perretti M, Flower R J. Anti-inflammatory role of the murineformyl-peptide receptor 2: Ligand-specific effects on leukocyteresponses and experimental inflammation. Journal of Immunology 2010;184: 2611-2619. Gavins F N E, Hughes E L, Buss NAPS, Holloway P M,Getting S J, Buckingham J C. Leukocyte recruitment in the brain insepsis: involvement of the annexin1 FPR2/ALX anti-inflammatory system.FASEB 2012; 26: 1-13).

Activation of FPR2 by lipoxin A4 or its analogs and by Annexin I proteinhas been shown to result in anti-inflammatory activity by promotingactive resolution of inflammation which involves inhibition ofpolymorphonuclear neutrophils (PMNs) and eosinophils migration and alsostimulating monocyte migration enabling clearance of apoptotic cellsfrom the site of inflammation in a nonphlogistic manner (Gavins F N E,Hughes E L, Buss NAPS, Holloway P M, Getting S J, Buckingham J C.Leukocyte recruitment in the brain in sepsis: involvement of theannexin1 FPR2/ALX anti-inflammatory system. FASEB 2012; 26: 1-13,Maderna P, Cottell D C, Toivonen T, Dufton N, Dalli J, Perretti M,Godson C. FPR2/ALX receptor expression and internalization are criticalfor lipoxin A4 and annexin-derived peptide-stimulated phagocytosis.FASEB 2010; 24: 4240-4249). In addition, FPR2 has been shown to inhibitnatural killer (NK) cytotoxicity and promote activation of T cells whichfurther contributes to down regulation of tissue damaging inflammatorysignals.

FPR2 interaction with LXA4 and Annexin has been shown to be beneficialin experimental models of dermal inflammation, angiogenesis, epithelialmigration, edema, alopecia, ischemia reperfusion and ocularinflammation, such as endotoxin-induced uveitis and corneal woundhealing (Reville K, Cream J K, Vivers S, Dransfield I, Godson C. LipoxinA4 redistributes Mysoin IIA and Cdc42 in macrophages: Implications forphagocytosis of apoptotic leukocytes. Journal of Immunology 2006; 176:1878-1888; Serhan C. Resolution phase of inflammation: Novel endogenousanti-inflammatory and proresolving lipid mediators and pathways. Annualreviews of Immunology 2007; 25: 101-137.; Medeiros R, Rodrigues G B,Figueiredo C P, Rodrigues E B, Grumman A Jr, Menezes-de-Lima O Jr,Passos G F, Calixto J B. Molecular mechanisms of topicalanti-inflammatory effects of lipoxin A(4) in endotoxin-induced uveitis.Molecular Pharmacology 2008; 74: 154-161; Gronert K, Maheshwari N, KhanN, Hassan I R, Dunn M, Schwartzmann M L. A role for the mouse12/15-lipoxygenase pathways in promoting epithelial wound healing andhost defense. Journal of Biological Chemistry 2005; 280: 15267-15278;Gronert K. Lipoxins in the eye and their role in wound healing.Prostaglandins, Leukotrienes and Essential fatty Acids. 2005; 73:221-229; Takano T, Fiore S, Maddox J F, Brady H R, Petasis N A, Serhan CN. Asprin-triggered 15-epi-lipoxin A4 and LXA4 stable analogues arepotent inhibitors of acute inflammation: evidence for anti-inflammatoryreceptors. Journal of Experimental Medicine 1997; 185: 1693-1704.; LeoniG, Alam A, Neumann P A, Lambeth J D, Cheng G, McCoy J, Hilgarth R S,Kundu K, Murthy N, Kusters D, Reutelingsperger C, Perretti M, Parkos CA, Neish A S, Nusrat A. Annexin A1, formyl peptide receptor, and NOX1orchestrate epithelial repair. Journal of Clinical Investigation. 2013;123:443-54; Leedom A, Sullivan A B, Dong B, Lau D, Gronert K. EndogenousLXA4 circuits are determinants of pathological angiogenesis in responseto chronic injury. American Journal of Pathology 2010; 176: 74-84;Tsuruki T, Takahata K, Yoshikawa M. Mechanism of the protective effectof intraperitoneally administered agonists for formyl peptide receptorsagainst chemotherapy-induced alopecia. Biosci BiotechnologyBiochemistry. 2007; 71:1198-202).

Pharmaceutical utility of lipoxin A4 and its analogs are hampered byinherent physicochemical properties of the natural poly-olefinic naturalproduct. Therefore, small molecule anti-inflammatory agonists of FPR2would have a wide variety of therapeutic benefit in inflammatorydisorders, including inflammatory disorders in the eye. Targeting FPR2selectively would also have benefits of reduced side effects as comparedto more broad acting anti-inflammatories such as steroids or NSAIDswhich have significant side effects of elevated IOP and delays in woundhealing in the eye. FPR2 is also expressed in ocular tissues in thecornea and also the posterior of eye, in addition to the inflammatorycells that migrate into the ocular tissues.

Targeting FPR2 selectively would also have benefits in skin woundhealing given its potent anti-inflammatory and pro-epithelial repairrole. In addition, some skin diseases have been shown to have anabnormal expression of LL37, a pro-inflammatory cathelicidin which hasbeen shown to be a natural ligand of FPR2. In the chronic inflammatorydisease rosacea, LL37 is highly expressed and is believed to play a keyrole in the pathogenesis (Yamasaki K, Di Nardo A, Bardan A, Murakami M,Ohtake T, Coda A, Dorschner R A, Bonnart C, Descargues P, Hovnanian A,Morhenn V B, Gallo R L. Increased serine protease activity andcathelicidin promotes skin inflammation in rosacea. Nature Medicine.2007; 13:975-80).

FPR2 thus represents an important novel pro-resolutionary moleculartarget for the development of new therapeutic agents in diseases orconditions with excessive inflammatory responses.

U.S. Pat. No. 8,492,556 teaches 2,5-dioxoimidazolidin-1-yl-3-phenylureaderivatives as formyl peptide modulators like-1 receptor modulators.

SUMMARY OF THE INVENTION

A group of novel compounds, which are potent and selective FPR2modulators, has been discovered. As such, the compounds described hereinare useful in treating a wide variety of disorders associated withmodulation of FPR2 receptor. The term “modulator” as used herein,includes but is not limited to: receptor agonist, antagonist, inverseagonist, inverse antagonist, partial agonist, and partial antagonist.

This invention describes compounds of Formula I, which have FPR2receptor biological activity. The compounds in accordance with thepresent invention are thus of use in medicine, for example, in thetreatment of humans with diseases and conditions that are alleviated byFPR2 modulation.

In one aspect, the invention provides a compound having Formula I:

-   -   wherein:    -   R¹ is substituted or unsubstituted C₁₋₈ alkyl, substituted or        unsubstituted C₃₋₈ cycloalkyl, substituted or unsubstituted        C₆-C₁₀ aryl, or substituted or unsubstituted heterocycle;    -   R² is H, or substituted or unsubstituted C₁₋₈alkyl;    -   R³ is O or NR⁵;    -   n is 1 or 2;    -   m is 1 or 2;    -   R⁴ is —C(O)R⁶, —P(O)(OR⁷)(OR⁸), —P(O)(OR⁹)(NR¹⁰R¹¹), —S(O)R¹² or        —SO₂R¹³;    -   R⁵ is H or substituted or unsubstituted C₁₋₈alkyl;    -   R⁶ is —OC₁₋₈alkyl or —OH;    -   R⁷ is H or substituted or unsubstituted C₁₋₈alkyl;    -   R⁸ is H or substituted or unsubstituted C₁₋₈alkyl;    -   R⁹ is H or substituted or unsubstituted C₁₋₈alkyl;    -   R¹⁰ is H or substituted or unsubstituted C₁₋₈alkyl;    -   R¹¹ is H or substituted or unsubstituted C₁₋₈alkyl;    -   R¹² is H, —OH, —NR¹⁴R¹⁵ or substituted or unsubstituted        C₁₋₈alkyl;    -   R¹³ is H or substituted or unsubstituted C₁₋₈alkyl;    -   R¹⁴ is H or substituted or unsubstituted C₁₋₈alkyl; and    -   R¹⁵ is H or substituted or unsubstituted C₁₋₈alkyl;    -   or an enantiomer, diastereomer or tautomer thereof;    -   or a zwitterion or pharmaceutically acceptable salt of any one        of the foregoing.

The term “alkyl”, as used herein, refers to saturated, monovalent ordivalent hydrocarbon moieties having linear or branched moieties orcombinations thereof and containing 1 to 8 carbon atoms (i.e.,C₁₋₈alkyl), one methylene (—CH₂—) group of the alkyl group can bereplaced by oxygen, sulfur, sulfoxide, —N(R^(x))— (wherein R^(x) is H,OH, or optionally substituted C₁₋₈ alkyl), carbonyl, carboxyl, sulfonyl,sulfate, sulfonate, amide, sulfonamide, by a divalent C₃₋₈ cycloalkyl,by a divalent heterocycle, or by a divalent aryl group. Alkyl groups canhave one or more chiral centers. Alkyl groups can be independentlysubstituted with one or more halogen atoms, hydroxyl groups,C₃₋₈cycloalkyl groups, amino groups, heterocyclic groups, optionallysubstituted aryl groups, carboxylic acid groups, phosphonic acid groups,phosphonate groups, sulphonic acid groups, phosphoric acid groups, nitrogroups, amide groups, ester groups, ether groups, ketone groups and/orsulfonamide groups. In some embodiments, the alkyl is a C₁₋₄alkyl, whichrefers to saturated, monovalent or divalent hydrocarbon moieties havinglinear or branched moieties or combinations thereof and containing 1 to4 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl,tert-butyl, isobutyl and sec-butyl.

The term “cycloalkyl”, as used herein, refers to a monovalent ordivalent group of 3 to 8 carbon atoms derived from a saturated cyclichydrocarbon. Cycloalkyl groups can be monocyclic or polycyclic. Onemethylene (—CH₂—) group, of the cycloalkyl can be replaced by, carbonyl.Cycloalkyl can be independently substituted by halogen atoms,sulfonyl(C₁₋₈alky) groups, sulfoxide(C₁₋₈alky) groups, sulfonamidegroups, nitro groups, cyano groups, —OC₁₋₈ alkyl groups, —SH, —SC₁₋₈alkyl groups, —C₁₋₈ alkyl groups, amide groups, ester groups, ethergroups, ketone groups, alkylamino groups, amino groups, aryl groups,C₃₋₈ cycloalkyl groups, carboxylic acid groups and/or hydroxyl groups.

The term “cycloalkenyl”, as used herein, refers to a monovalent ordivalent group of 3 to 8 carbon atoms derived from a saturatedcycloalkyl having at least one double bond. cycloalkenyl groups can bemonocyclic or polycyclic. One methylene (—CH₂—) group, of thecycloalkenyl can be replaced by a divalent C₃₋₈ cycloalkyl, by adivalent heterocycle, or by a divalent aryl group. cycloalkenyl groupscan be independently substituted by halogen atoms, sulfonyl groups,sulfoxide groups, nitro groups, cyano groups, —OC₁₋₈ alkyl groups,—SC₁₋₈ alkyl groups, —C₁₋₈ alkyl groups, ketone groups, alkylaminogroups, amide groups, ester groups, ether groups, amino groups, arylgroups, sulfonamide groups, C₃₋₈ cycloalkyl groups, carboxylic acidgroups and/or hydroxyl groups.

The term “halogen”, as used herein, refers to an atom of fluorine,chlorine, bromine, iodine.

The term “alkenyl”, as used herein, refers to a monovalent or divalenthydrocarbon radical having 2 to 6 carbon atoms, derived from a saturatedalkyl, having at least one double bond. One methylene (—CH₂—) group ofthe alkenyl can be replaced by oxygen, sulfur, sulfoxide, —N(R^(x))—(wherein R^(x) is H, OH, or optionally substituted C₁₋₈ alkyl),carbonyl, carboxyl, sulfonyl, sulfate, sulfonate, amide, sulfonamide, bya divalent C₃₋₈ cycloalkyl, by a divalent heterocycle, or by a divalentaryl group. C₂₋₆ alkenyl can be in the E or Z configuration. Alkenylgroups can be substituted by alkyl groups, as defined above or byhalogen atoms.

The term “alkynyl”, as used herein, refers to a monovalent or divalenthydrocarbon radical having 2 to 6 carbon atoms, derived from a saturatedalkyl, having at least one triple bond. One methylene (—CH₂—) group, ofthe alkynyl can be replaced by oxygen, sulfur, sulfoxide, —N(R^(x))—(wherein R^(x) is H, OH, or optionally substituted C₁₋₈ alkyl),carbonyl, carboxyl, sulfonyl, sulfate, sulfonate, amide, sulfonamide, bya divalent C₃₋₈ cycloalkyl, by a divalent heterocycle, or by a divalentaryl group. Alkynyl groups can be substituted by alkyl groups, asdefined above, and/or by halogen atoms.

The term “heterocycle” as used herein, refers to a 3 to 10 memberedring, which can be aromatic or non-aromatic, saturated or unsaturated,containing at least one heteroatom selected from oxygen, nitrogen,sulfur or combinations of at least two thereof, interrupting thecarbocyclic ring structure. The heterocyclic ring can be interrupted bya C═O; the S and N heteroatoms can be oxidized. Heterocycles can bemonocyclic or polycyclic. Heterocyclic ring moieties can be substitutedby halogen atoms, sulfonyl groups, sulfoxide groups, sulfonamide groups,nitro groups, cyano groups, —OC₁₋₈ alkyl groups, —SC₁₋₆ alkyl groups,—C₁₋₆ alkyl groups, ketone groups, alkylamino groups, amino groups, arylgroups, amide groups, ester groups, ether groups, C₃₋₈ cycloalkylgroups, carboxylic acid groups and/or hydroxyl groups.

The term “aryl” as used herein, refers to an organic moiety derived froman aromatic hydrocarbon consisting of a ring containing 6 to 10 carbonatoms by removal of one hydrogen. Aryls can be monocyclic or polycyclic.One or more hydrogen atoms can be independently substituted by halogenatoms, sulfonyl(C₁₋₈ alkyl) groups, sulfoxide(C₁₋₈ alkyl) groups,sulfonamide groups, carboxylic acid groups, C₁₋₈ alkyl carboxylate(ester) groups, amide groups, nitro groups, cyano groups, —OC₁₋₈ alkylgroups, —SH, —SC₁₋₈ alkyl groups, —C₁₋₈ alkyl groups, ether groups,ketone groups, aldehydes groups, sulfonamide groups, alkylamino groups,ester groups, amino groups, aryl groups, C₃₋₈ cycloalkyl groups and/orhydroxyl groups.

The term “hydroxyl” as used herein, represents a group of formula “—OH”.

The term “carbonyl” as used herein, represents a group of formula“—C(O)—”.

The term “aldehyde” as used herein, represents a group of formula“—C(O)H”.

The term “ketone” as used herein, represents an organic compound havinga carbonyl group linked to a carbon atom such as —C(O)R^(x) whereinR^(x) can be alkyl, aryl, cycloalkyl, cycloalkenyl or heterocycle, asdefined above.

The term “ether” as used herein, represents a group of formula —(O)R^(x)wherein R^(x) is alkyl, aryl, cycloalkyl, cycloalkenyl or heterocycle,as defined above.

The term “amine” as used herein, represents a group of formula“—NR^(x)R^(y)”, wherein R^(x) and R^(y) can be the same or independentlyH, alkyl, aryl, cycloalkyl, cycloalkenyl or heterocycle, as definedabove.

The term “ethyl” as used herein, represents a group of formula “—C₂H₅”.

The term “carboxyl” as used herein, represents a group of formula“—C(O)O—”.

The term “sulfonyl” as used herein, represents a group of formula“—SO₂”.

The term “sulfate” as used herein, represents a group of formula“—OS(O)₂O—”.

The term “sulfonate” as used herein, represents a group of the formula“—S(O)₂O—”.

The term “carboxylic acid” as used herein, represents a group of formula“—C(O)OH”.

The term “ester” as used herein, represents a group of formula“—C(O)OR^(x)”, wherein R^(x) is alkyl, aryl, cycloalkyl, cycloalkenyl orheterocycle, as defined above.

The term “nitro” as used herein, represents a group of formula “—NO₂”.

The term “cyano” as used herein, represents a group of formula “—CN”.

The term “amide” as used herein, represents a group of formula“—C(O)NR^(x)R^(y),” wherein R^(x) and R^(y) can be the same orindependently H, alkyl, aryl, cycloalkyl, cycloalkenyl or heterocycle,as defined above.

The term “sulfonamide” as used herein, represents a group of formula“—S(O)₂NR^(x)R^(y)” wherein R^(x) and R^(y) can be the same orindependently H, alkyl, aryl, cycloalkyl, cycloalkenyl or heterocycle,as defined above.

The term “sulfoxide” as used herein, represents a group of formula“—S(O)—”.

The term “phosphonic acid” as used herein, represents a group of formula“—P(O)(OH)₂”.

The term “phosphonate” as used herein, represents a group of formulae“—P(O)(OH)(OC₁₋₈ alkyl)” or “—P(O)(OC₁₋₈ alkyl)(OC₁₋₈ alkyl)”.

The term “phosphoric acid” as used herein, represents a group of formula“—OP(O)(OH)₂”.

The term “sulphonic acid” as used herein, represents a group of formula“—S(O)₂OH”.

The formula “H”, as used herein, represents a hydrogen atom.

The formula “O”, as used herein, represents an oxygen atom.

The formula “N”, as used herein, represents a nitrogen atom.

The formula “S”, as used herein, represents a sulfur atom.

In one exemplary embodiment, a compound of the invention is Ethyl3-{[2-(1-{[(4-bromophenyl)carbamoyl]amino}-4-ethyl-2,5-dioxoimidazolidin-4-yl)ethyl]amino}propanoate.

Some compounds of Formula I and some of their intermediates have atleast one asymmetric center in their structure. This asymmetric centermay be present in an R or S configuration, said R and S notation is usedin correspondence with the rules described in Pure Appl. Chem. (1976),45, 11-13.

The term “pharmaceutically acceptable salts” refers to salts orcomplexes that retain the desired biological activity of the aboveidentified compounds and exhibit minimal or no undesired toxicologicaleffects. The “pharmaceutically acceptable salts” according to theinvention include therapeutically active, non-toxic base or acid saltforms, which the compounds of Formula I are able to form.

The acid addition salt form of a compound of Formula I that occurs inits free form as a base can be obtained by treating the free base withan appropriate acid such as an inorganic acid, for example, hydrochloricacid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid andthe like; or an organic acid such as for example, acetic acid,hydroxyacetic acid, propanoic acid, lactic acid, pyruvic acid, malonicacid, fumaric acid, maleic acid, oxalic acid, tartaric acid, succinicacid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid,citric acid, methylsulfonic acid, ethanesulfonic acid, benzenesulfonicacid, formic and the like (Handbook of Pharmaceutical Salts, P. HeinrichStahl & Camille G. Wermuth (Eds), Verlag Helvetica Chimica Acta-Zürich,2002, 329-345).

The base addition salt form of a compound of Formula I that occurs inits acid form can be obtained by treating the acid with an appropriatebase such as an inorganic base, for example, sodium hydroxide, magnesiumhydroxide, potassium hydroxide, calcium hydroxide, ammonia and the like;or an organic base such as for example, L-Arginine, ethanolamine,betaine, benzathine, morpholine and the like. (Handbook ofPharmaceutical Salts, P. Heinrich Stahl & Camille G. Wermuth (Eds),Verlag Helvetica Chimica Acta-Zürich, 2002, 329-345).

The compounds of the invention are indicated for use in treating orpreventing conditions in which there is likely to be a componentinvolving the N-formyl peptide receptor 2.

In another embodiment, there are provided pharmaceutical compositionsincluding at least one compound of the invention in a pharmaceuticallyacceptable carrier.

In a further embodiment of the invention, there are provided methods fortreating disorders associated with modulation of the N-formyl peptide 2receptor. Such methods can be performed, for example, by administeringto a subject in need thereof a pharmaceutical composition containing atherapeutically effective amount of at least one compound of theinvention.

Therapeutic utilities of the N-formyl peptide 2 receptor modulators areocular inflammatory diseases and conditions including, but not limitedto, wet and dry age-related macular degeneration (ARMD), uveitis, dryeye, keratitis, allergic eye disease and conditions affecting theposterior part of the eye, such as maculopathies and retinaldegeneration including non-exudative age related macular degeneration,exudative age related macular degeneration, choroidalneovascularization, diabetic retinopathy (proliferative), retinopathy ofprematurity (ROP), acute macular neuroretinopathy, central serouschorioretinopathy, cystoid macular edema, and diabetic macular edema;infectious keratitis, herpetic keratitis, corneal angiogenesis,lymphangiogenesis, retinitis, choroiditis such as acute multifocalplacoid pigment epitheliopathy, Behcet's disease, birdshotretinochoroidopathy, infectious (syphilis, lyme, tuberculosis,toxoplasmosis), intermediate uveitis (pars planitis), multifocalchoroiditis, multiple evanescent white dot syndrome (mewds), ocularsarcoidosis, posterior scleritis, serpiginous choroiditis, subretinalfibrosis and uveitis syndrome, Vogt-Koyanagi- and Harada syndrome;vasuclar diseases/exudative diseases such as retinal arterial occlusivedisease, central retinal vein occlusion, cystoids macular edema,disseminated intravascular coagulopathy, branch retinal vein occlusion,hypertensive fundus changes, ocular ischemic syndrome, retinal arterialmicroaneurysms, Coat's disease, parafoveal telangiectasis, hemi-retinalvein occlusion, papillophlebitis, central retinal artery occlusion,branch retinal artery occlusion, carotid artery disease (CAD), frostedbranch angiitis, sickle cell retinopathy and other hemoglobinopathies,angioid streaks, familial exudative vitreoretinopathy, and Ealesdisease; traumatic/surgical conditions such as sympathetic ophthalmia,uveitic retinal disease, retinal detachment, trauma, post surgicalcorneal wound healing, post-cataract surgical inflammation, conditionscaused by laser, conditions caused by photodynamic therapy,photocoagulation, hypoperfusion during surgery, radiation retinopathy,and bone marrow transplant retinopathy; proliferative disorders such asproliferative vitreal retinopathy and epiretinal membranes, andproliferative diabetic retinopathy; infectious disorders such as ocularhistoplasmosis, ocular toxocariasis, presumed ocular histoplasmosissyndrome (PONS), endophthalmitis, toxoplasmosis, retinal diseasesassociated with HIV infection, choroidal disease associate with HIVinfection, uveitic disease associate with HIV infection, viralretinitis, acute retinal necrosis, progressive outer retinal necrosis,fungal retinal diseases, ocular syphilis, ocular tuberculosis, diffuseunilateral subacute neuroretinitis, and myiasis; genetic disorders suchas retinitis pigmentosa, systemic disorders with associated retinaldystrophies, congenital stationary night blindness, cone dystrophies,Stargardt's disease and fundus flavimaculatus, Best's disease, patterndystrophy of the retinal pigmented epithelium, X-linked retinoschisis,Sorsby's fundus dystrophy, benign concentric maculopathy, Bietti'scrystalline dystrophy, and pseudoxanthoma elasticum; retinal tears/holessuch as retinal detachment, macular hole, and giant retinal tear; tumorssuch as retinal disease associated with tumors, congenital hypertrophyof the retinal pigmented epithelium, posterior uveal melanoma, choroidalhemangioma, choroidal osteoma, choroidal metastasis, combined hamartomaof the retina and retinal pigmented epithelium, retinoblastoma,vasoproliferative tumors of the ocular fundus, retinal astrocytoma, andintraocular lymphoid tumors; and miscellaneous other diseases affectingthe posterior part of the eye such as punctate inner choroidopathy,acute posterior multifocal placoid pigment epitheliopathy, myopicretinal degeneration, and acute retinal pigement epitheliitis, systemicinflammatory diseases such as stroke, coronary artery disease,obstructive airway diseases, HIV-mediated retroviral infections,cardiovascular disorders including coronary artery disease,neuroinflammation, neurological disorders, pain and immunologicaldisorders, rheumatoid arthritis and related inflammatory disorders,asthma, allergic disorders, inflammation, systemic lupus erythematosus,CNS disorders such as Alzheimer's disease, arthritis, sepsis,inflammatory bowel disease, cachexia, angina pectoris, post-surgicalcorneal inflammation, blepharitis, meibomian gland dysfunction;glaucoma, branch vein occlusion, Best's vitelliform macular degenartion,retinitis pigmentosa, proliferative vitreoretinopathy (PVR), and anyother degenerative disease of either the photoreceptors or the RPE(Perretti, Mauro et al. Pharmacology & Therapeutics 127 (2010) 175-188).Therapeutic utilities of the N-formyl peptide 2 receptor modulators alsoinclude the treatment of dermal inflammation and dermal diseasesincluding but not limited to dermal wound healing, hypertrophic scars,keloids, burns, rosacea, atopic dermatitis, acne, psoriasis, seborrheicdermatitis, actinic keratoses, basal cell carcinoma, squamous cellcarcinoma, melanoma, viral warts, photoaging, photodamage, melasma,post-inflammatory hyperpigmentation, disorders of pigmentation,alopecia, scarring and non-scarring forms.

The compounds described herein are useful for the treatment of mammals,including humans, with a range of conditions and diseases that arealleviated by FPR2 modulation: including, but not limited to thetreatment of ocular inflammatory diseases: wet and dry age-relatedmacular degeneration (ARMD), uveitis, dry eye, keratitis, allergic eyedisease and conditions affecting the posterior part of the eye, such asmaculopathies and retinal degeneration including non-exudative agerelated macular degeneration, exudative age related maculardegeneration, choroidal neovascularization, diabetic retinopathy(proliferative), retinopathy of prematurity (ROP), acute macularneuroretinopathy, central serous chorioretinopathy, cystoid macularedema, and diabetic macular edema; infectious keratitis, herpetickeratitis, corneal angiogenesis, lymphangiogenesis, retinitis,choroiditis such as acute multifocal placoid pigment epitheliopathy,Behcet's disease, birdshot retinochoroidopathy, infectious (syphilis,lyme, tuberculosis, toxoplasmosis), intermediate uveitis (parsplanitis), multifocal choroiditis, multiple evanescent white dotsyndrome (mewds), ocular sarcoidosis, posterior scleritis, serpiginouschoroiditis, subretinal fibrosis and uveitis syndrome, Vogt-Koyanagi-and Harada syndrome; vasuclar diseases/exudative diseases such asretinal arterial occlusive disease, central retinal vein occlusion,cystoids macular edema, disseminated intravascular coagulopathy, branchretinal vein occlusion, hypertensive fundus changes, ocular ischemicsyndrome, retinal arterial microaneurysms, Coat's disease, parafovealtelangiectasis, hemi-retinal vein occlusion, papillophlebitis, centralretinal artery occlusion, branch retinal artery occlusion, carotidartery disease (CAD), frosted branch angiitis, sickle cell retinopathyand other hemoglobinopathies, angioid streaks, familial exudativevitreoretinopathy, and Eales disease; traumatic/surgical conditions suchas sympathetic ophthalmia, uveitic retinal disease, retinal detachment,trauma, post surgical corneal wound healing, post-cataract surgicalinflammation, conditions caused by laser, conditions caused byphotodynamic therapy, photocoagulation, hypoperfusion during surgery,radiation retinopathy, and bone marrow transplant retinopathy;proliferative disorders such as proliferative vitreal retinopathy andepiretinal membranes, and proliferative diabetic retinopathy; infectiousdisorders such as ocular histoplasmosis, ocular toxocariasis, presumedocular histoplasmosis syndrome (PONS), endophthalmitis, toxoplasmosis,retinal diseases associated with HIV infection, choroidal diseaseassociate with HIV infection, uveitic disease associate with HIVinfection, viral retinitis, acute retinal necrosis, progressive outerretinal necrosis, fungal retinal diseases, ocular syphilis, oculartuberculosis, diffuse unilateral subacute neuroretinitis, and myiasis;genetic disorders such as retinitis pigmentosa, systemic disorders withassociated retinal dystrophies, congenital stationary night blindness,cone dystrophies, Stargardt's disease and fundus flavimaculatus, Best'sdisease, pattern dystrophy of the retinal pigmented epithelium, X-linkedretinoschisis, Sorsby's fundus dystrophy, benign concentric maculopathy,Bietti's crystalline dystrophy, and pseudoxanthoma elasticum; retinaltears/holes such as retinal detachment, macular hole, and giant retinaltear; tumors such as retinal disease associated with tumors, congenitalhypertrophy of the retinal pigmented epithelium, posterior uvealmelanoma, choroidal hemangioma, choroidal osteoma, choroidal metastasis,combined hamartoma of the retina and retinal pigmented epithelium,retinoblastoma, vasoproliferative tumors of the ocular fundus, retinalastrocytoma, and intraocular lymphoid tumors; and miscellaneous otherdiseases affecting the posterior part of the eye such as punctate innerchoroidopathy, acute posterior multifocal placoid pigmentepitheliopathy, myopic retinal degeneration, and acute retinal pigementepitheliitis, systemic inflammatory diseases such as stroke, coronaryartery disease, obstructive airway diseases, HIV-mediated retroviralinfections, cardiovascular disorders including coronary artery disease,neuroinflammation, neurological disorders, pain and immunologicaldisorders, rheumatoid arthritis and related inflammatory disorders,asthma, allergic disorders, inflammation, systemic lupus erythematosus,CNS disorders such as Alzheimer's disease, arthritis, sepsis,inflammatory bowel disease, cachexia, angina pectoris, post-surgicalcorneal inflammation, blepharitis, meibomian gland dysfunction;glaucoma, branch vein occlusion, Best's vitelliform macular degenartion,retinitis pigmentosa, proliferative vitreoretinopathy (PVR), and anyother degenerative disease of either the photoreceptors or the RPE(Perretti, Mauro et al. Pharmacology & Therapeutics 127 (2010) 175-188).These compounds are useful for the treatment of dermal inflammation anddermal diseases including but not limited to dermal wound healing,hypertrophic scars, keloids, burns, rosacea, atopic dermatitis, acne,psoriasis, seborrheic dermatitis, actinic keratoses, basal cellcarcinoma, squamous cell carcinoma, melanoma, viral warts, photoaging,photodamage, melasma, post-inflammatory hyperpigmentation, disorders ofpigmentation, alopecia, scarring and non-scarring forms.

In still another embodiment of the invention, there are provided methodsfor treating disorders associated with modulation of the FPR2 receptor.Such methods can be performed, for example, by administering to asubject in need thereof a therapeutically effective amount of at leastone compound of the invention, or any combination thereof, orpharmaceutically acceptable salts, individual enantiomers, and/ordiastereomers thereof.

The present invention concerns the use of a compound of Formula I or apharmaceutically acceptable salt thereof, for the manufacture of amedicament for the treatment of ocular inflammatory diseases including,but not limited to, wet and dry age-related macular degeneration (ARMD),uveitis, dry eye, keratitis, allergic eye disease and conditionsaffecting the posterior part of the eye, such as maculopathies andretinal degeneration including non-exudative age related maculardegeneration, exudative age related macular degeneration, choroidalneovascularization, diabetic retinopathy (proliferative), retinopathy ofprematurity (ROP), acute macular neuroretinopathy, central serouschorioretinopathy, cystoid macular edema, and diabetic macular edema;infectious keratitis, herpetic keratitis, corneal angiogenesis,lymphangiogenesis, uveitis, retinitis, and choroiditis such as acutemultifocal placoid pigment epitheliopathy, Behcet's disease, birdshotretinochoroidopathy, infectious (syphilis, lyme, tuberculosis,toxoplasmosis) intermediate uveitis (pars planitis), multifocalchoroiditis, multiple evanescent white dot syndrome (mewds), ocularsarcoidosis, posterior scleritis, serpiginous choroiditis, subretinalfibrosis and uveitis syndrome, Vogt-Koyanagi- and Harada syndrome;vasuclar diseases/exudative diseases such as retinal arterial occlusivedisease, central retinal vein occlusion, cystoids macular edema,disseminated intravascular coagulopathy, branch retinal vein occlusion,hypertensive fundus changes, ocular ischemic syndrome, retinal arterialmicroaneurysms, Coat's disease, parafoveal telangiectasis, hemi-retinalvein occlusion, papillophlebitis, central retinal artery occlusion,branch retinal artery occlusion, carotid artery disease (CAD), frostedbranch angiitis, sickle cell retinopathy and other hemoglobinopathies,angioid streaks, familial exudative vitreoretinopathy, and Ealesdisease; traumatic/surgical conditions such as sympathetic ophthalmia,uveitic retinal disease, retinal detachment, trauma, post surgicalcorneal wound healing or inflammation, post-cataract surgicalinflammation, wet and dry age-related macular degeneration (ARMD),conditions caused by laser, conditions caused by photodynamic therapy,photocoagulation, hypoperfusion during surgery, radiation retinopathy,and bone marrow transplant retinopathy; proliferative disorders such asproliferative vitreal retinopathy and epiretinal membranes, andproliferative diabetic retinopathy; infectious disorders such as ocularhistoplasmosis, ocular toxocariasis, presumed ocular histoplasmosissyndrome (PONS), endophthalmitis, toxoplasmosis, retinal diseasesassociated with HIV infection, choroidal disease associate with HIVinfection, uveitic disease associate with HIV infection, viralretinitis, acute retinal necrosis, progressive outer retinal necrosis,fungal retinal diseases, ocular syphilis, ocular tuberculosis, diffuseunilateral subacute neuroretinitis, and myiasis; genetic disorders suchas retinitis pigmentosa, systemic disorders with associated retinaldystrophies, congenital stationary night blindness, cone dystrophies,Stargardt's disease and fundus flavimaculatus, Best's disease, patterndystrophy of the retinal pigmented epithelium, X-linked retinoschisis,Sorsby's fundus dystrophy, benign concentric maculopathy, Bietti'scrystalline dystrophy, and pseudoxanthoma elasticum; retinal tears/holessuch as retinal detachment, macular hole, and giant retinal tear; tumorssuch as retinal disease associated with tumors, congenital hypertrophyof the retinal pigmented epithelium, posterior uveal melanoma, choroidalhemangioma, choroidal osteoma, choroidal metastasis, combined hamartomaof the retina and retinal pigmented epithelium, retinoblastoma,vasoproliferative tumors of the ocular fundus, retinal astrocytoma, andintraocular lymphoid tumors; and miscellaneous other diseases affectingthe posterior part of the eye such as punctate inner choroidopathy,acute posterior multifocal placoid pigment epitheliopathy, myopicretinal degeneration, and acute retinal pigement epitheliitis, systemicinflammatory diseases such as stroke, coronary artery disease,obstructive airway diseases, HIV-mediated retroviral infections,cardiovascular disorders including coronary artery disease,neuroinflammation, neurological disorders, pain and immunologicaldisorders, rheumatoid arthritis and related inflammatory disorders,asthma, allergic disorders, inflammation, systemic lupus erythematosus,CNS disorders such as Alzheimer's disease, arthritis, sepsis,inflammatory bowel disease, cachexia, angina pectoris, post-surgicalcorneal inflammation, blepharitis, meibomian gland dysfunction,glaucoma, branch vein occlusion, Best's vitelliform macular degenartion,retinitis pigmentosa, proliferative vitreoretinopathy (PVR), and anyother degenerative disease of either the photoreceptors or the RPE. Thepresent invention further concerns the use of a compound of Formula I ora pharmaceutically acceptable salt thereof, for the manufacture of amedicament for the treatment of dermal inflammation and dermal diseasesor conditions including but not limited to dermal wound healing,hypertrophic scars, keloids, burns, rosacea, atopic dermatitis, acne,psoriasis, seborrheic dermatitis, actinic keratoses, basal cellcarcinoma, squamous cell carcinoma, melanoma, viral warts, photoaging,photodamage, melasma, post-inflammatory hyperpigmentation, disorders ofpigmentation, alopecia, scarring and non-scarring forms.

The actual amount of the compound to be administered in any given casewill be determined by a physician taking into account the relevantcircumstances, such as the severity of the condition, the age and weightof the patient, the patient's general physical condition, the cause ofthe condition, and the route of administration.

The patient will be administered the compound orally in any acceptableform, such as a tablet, liquid, capsule, powder and the like, or otherroutes may be desirable or necessary, particularly if the patientsuffers from nausea. Such other routes may include, without exception,transdermal, parenteral, subcutaneous, intranasal, via an implant stent,intrathecal, intravitreal, topical to the eye, back to the eye,intramuscular, intravenous, and intrarectal modes of delivery.Additionally, the formulations may be designed to delay release of theactive compound over a given period of time, or to carefully control theamount of drug released at a given time during the course of therapy.

In another embodiment of the invention, there are providedpharmaceutical compositions including at least one compound of theinvention in a pharmaceutically acceptable carrier thereof. The phrase“pharmaceutically acceptable” means the carrier, diluent or excipientmust be compatible with the other ingredients of the formulation and notdeleterious to the recipient thereof.

Pharmaceutical compositions of the present invention can be used in theform of a solid, a solution, an emulsion, a dispersion, a patch, amicelle, a liposome, and the like, wherein the resulting compositioncontains one or more compounds of the present invention, as an activeingredient, in admixture with an organic or inorganic carrier orexcipient suitable for enteral or parenteral applications. Inventioncompounds may be combined, for example, with the usual non-toxic,pharmaceutically acceptable carriers for tablets, pellets, capsules,suppositories, solutions, emulsions, suspensions, and any other formsuitable for use. The carriers which can be used include glucose,lactose, gum acacia, gelatin, mannitol, starch paste, magnesiumtrisilicate, talc, corn starch, keratin, colloidal silica, potatostarch, urea, medium chain length triglycerides, dextrans, and othercarriers suitable for use in manufacturing preparations, in solid,semisolid, or liquid form. In addition, auxiliary, stabilizing,thickening and coloring agents and perfumes may be used. Inventioncompounds are included in the pharmaceutical composition in an amountsufficient to produce the desired effect upon the process or diseasecondition.

Pharmaceutical compositions containing invention compounds may be in aform suitable for oral use, for example, as tablets, troches, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsions,hard or soft capsules, or syrups or elixirs. Compositions intended fororal use may be prepared according to any method known in the art forthe manufacture of pharmaceutical compositions and such compositions maycontain one or more agents selected from the group consisting of asweetening agent such as sucrose, lactose, or saccharin, flavoringagents such as peppermint, oil of wintergreen or cherry, coloring agentsand preserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets containing invention compounds inadmixture with non-toxic pharmaceutically acceptable excipients may alsobe manufactured by known methods. The excipients used may be, forexample, (1) inert diluents such as calcium carbonate, lactose, calciumphosphate or sodium phosphate; (2) granulating and disintegrating agentssuch as corn starch, potato starch or alginic acid; (3) binding agentssuch as gum tragacanth, corn starch, gelatin or acacia, and (4)lubricating agents such as magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed.

In some cases, formulations for oral use may be in the form of hardgelatin capsules wherein the invention compounds are mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin. They may also be in the form of soft gelatin capsules whereinthe invention compounds are mixed with water or an oil medium, forexample, peanut oil, liquid paraffin or olive oil.

The pharmaceutical compositions may be in the form of a sterileinjectable suspension. This suspension may be formulated according toknown methods using suitable dispersing or wetting agents and suspendingagents. The sterile injectable preparation may also be a sterileinjectable solution or suspension in a non-toxic parenterally-acceptablediluent or solvent, for example, as a solution in 1,3-butanediol.Sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides, fatty acids (including oleicacid), naturally occurring vegetable oils like sesame oil, coconut oil,peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like ethyloleate or the like. Buffers, preservatives, antioxidants, and the likecan be incorporated as required.

Pharmaceutical compositions containing invention compounds may be in aform suitable for topical use, for example, as oily suspensions, assolutions or suspensions in aqueous liquids or nonaqueous liquids, or asoil-in-water or water-in-oil liquid emulsions. Pharmaceuticalcompositions may be prepared by combining a therapeutically effectiveamount of at least one compound according to the present invention, or apharmaceutically acceptable salt thereof, as an active ingredient withconventional ophthalmically acceptable pharmaceutical excipients and bypreparation of unit dosage suitable for topical ocular use. Thetherapeutically efficient amount typically is between about 0.0001 andabout 5% (w/v), preferably about 0.001 to about 2.0% (w/v) in liquidformulations.

For ophthalmic application, preferably solutions are prepared using aphysiological saline solution as a major vehicle. The pH of suchophthalmic solutions should preferably be maintained between 4.5 and 8.0with an appropriate buffer system, a neutral pH being preferred but notessential. The formulations may also contain conventionalpharmaceutically acceptable preservatives, stabilizers and surfactants.Preferred preservatives that may be used in the pharmaceuticalcompositions of the present invention include, but are not limited to,benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetateand phenylmercuric nitrate. A preferred surfactant is, for example,Tween 80. Likewise, various preferred vehicles may be used in theophthalmic preparations of the present invention. These vehiclesinclude, but are not limited to, polyvinyl alcohol, povidone,hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose,hydroxyethyl cellulose cyclodextrin and purified water.

Tonicity adjustors may be added as needed or convenient. They include,but are not limited to, salts, particularly sodium chloride, potassiumchloride, mannitol and glycerin, or any other suitable ophthalmicallyacceptable tonicity adjustor.

Various buffers and means for adjusting pH may be used so long as theresulting preparation is ophthalmically acceptable. Accordingly, buffersinclude acetate buffers, citrate buffers, phosphate buffers and boratebuffers. Acids or bases may be used to adjust the pH of theseformulations as needed.

In a similar manner an ophthalmically acceptable antioxidant for use inthe present invention includes, but is not limited to, sodiummetabisulfite, sodium thiosulfate, acetylcysteine, butylatedhydroxyanisole and butylated hydroxytoluene.

Other excipient components which may be included in the ophthalmicpreparations are chelating agents. The preferred chelating agent isedentate disodium, although other chelating agents may also be used inplace of or in conjunction with it.

The ingredients are usually used in the following amounts:

Ingredient Amount (% w/v) active ingredient about 0.001-5 preservative 0-0.10 vehicle 0-40 tonicity adjustor 0-10 buffer 0.01-10   pH adjustorq.s. pH 4.5-7.8 antioxidant as needed surfactant as needed purifiedwater to make 100%.

The actual dose of the active compounds of the present invention dependson the specific compound, and on the condition to be treated; theselection of the appropriate dose is well within the knowledge of theskilled artisan.

The ophthalmic formulations of the present invention are convenientlypackaged in forms suitable for metered application, such as incontainers equipped with a dropper, to facilitate application to theeye. Containers suitable for dropwise application are usually made ofsuitable inert, non-toxic plastic material, and generally containbetween about 0.5 and about 15 ml solution. One package may contain oneor more unit doses. Especially preservative-free solutions are oftenformulated in non-resealable containers containing up to about ten,preferably up to about five unit doses, where a typical unit dose isfrom one to about 8 drops, preferably one to about 3 drops. The volumeof one drop usually is about 20-35 microliters.

The compounds of the invention may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionsmay be prepared by mixing the invention compounds with a suitablenon-irritating excipient, such as cocoa butter, synthetic glycerideesters of polyethylene glycols, which are solid at ordinarytemperatures, but liquefy and/or dissolve in the rectal cavity torelease the drug.

Since individual subjects may present a wide variation in severity ofsymptoms and each drug has its unique therapeutic characteristics, theprecise mode of administration and dosage employed for each subject isleft to the discretion of the practitioner.

The compounds and pharmaceutical compositions described herein areuseful as medicaments in mammals, including humans, for treatment ofdiseases and/or alleviations of conditions which are responsive totreatment by agonists or functional antagonists of the N-formyl peptide2 receptor. Thus, in further embodiments of the invention, there areprovided methods for treating a disorder associated with modulation ofthe N-formyl peptide 2 receptor. Such methods can be performed, forexample, by administering to a subject in need thereof a pharmaceuticalcomposition containing a therapeutically effective amount of at leastone invention compound. As used herein, the term “therapeuticallyeffective amount” means the amount of the pharmaceutical compositionthat will elicit the biological or medical response of a subject in needthereof that is being sought by the researcher, veterinarian, medicaldoctor or other clinician. In some embodiments, the subject in needthereof is a mammal. In some embodiments, the mammal is human.

The present invention concerns also processes for preparing thecompounds of Formula I. The compounds of Formula I according to theinvention can be prepared analogously to conventional methods asunderstood by the person skilled in the art of synthetic organicchemistry.

Synthetic Scheme 1 set forth below illustrates how the compoundsaccording to the invention can be made. Those skilled in the art will beable to routinely modify and/or adapt the following scheme to synthesizeany compounds of the invention covered by Formula I or their syntheticprecursors.

Compounds within the scope of the invention may be prepared as depictedin Scheme 1, wherein the variable groups R¹ through R⁴, n and m are asdefined in Formula I. In general, a1-(4-(2-aminoalkyl)-4-alkyl-2,5-dioxoimidazolidin-1-yl)-3-phenylurea canbe reacted with an appropriately substituted acrylester or a alkylbromide to provide compounds of Formula I. Details of certain specificchemical transformations are provided in the examples. Those skilled inthe art will be able to routinely modify and/or adapt the followingscheme to synthesize any compounds of the invention covered by FormulaI.

DRAWINGS

FIG. 1 shows the structure of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the invention claimed. As used herein, theuse of the singular includes the plural unless specifically statedotherwise.

It will be readily apparent to those skilled in the art that some of thecompounds of the invention may contain one or more asymmetric centers,such that the compounds may exist in enantiomeric as well as indiastereomeric forms. Unless it is specifically noted otherwise, thescope of the present invention includes all enantiomers, diastereomersand racemic mixtures. As will be evident to those skilled in the art,individual diasteroisomeric forms can be obtained by separation ofmixtures thereof in conventional manner; chromatographic separation maybe employed.

Some of the compounds of the invention may form salts withpharmaceutically acceptable acids or bases, and such pharmaceuticallyacceptable salts of the compounds described herein are also within thescope of the invention.

The present invention includes all pharmaceutically acceptableisotopically enriched compounds. Any compound of the invention maycontain one or more isotopic atoms enriched or different than thenatural ratio such as deuterium ²H (or D) in place of hydrogen ¹H (or H)or use of ¹³C enriched material in place of ¹²C and the like. Similarsubstitutions can be employed for N, O and S. The use of isotopes mayassist in analytical as well as therapeutic aspects of the invention.For example, use of deuterium may increase the in vivo half-life byaltering the metabolism (rate) of the compounds of the invention. Thesecompounds can be prepared in accord with the preparations described byuse of isotopically enriched reagents.

The following examples are for illustrative purposes only and are notintended, nor should they be construed as limiting the invention in anymanner. Those skilled in the art will appreciate that variations andmodifications of the following examples can be made without exceedingthe spirit or scope of the invention.

Non-limiting embodiments of the invention are as follows.

In embodiment (1), there is provided a compound represented by FormulaI:

-   -   wherein:    -   R¹ is substituted or unsubstituted C₁₋₈ alkyl, substituted or        unsubstituted C₃₋₈ cycloalkyl, substituted or unsubstituted        C₆-C₁₀ aryl, or substituted or unsubstituted heterocycle;    -   R² is H, or substituted or unsubstituted C₁₋₈alkyl;    -   R³ is O or NR⁵;    -   n is 1 or 2;    -   m is 1 or 2;    -   R⁴ is —C(O)R⁶, —P(O)(OR⁷)(OR⁸), —P(O)(OR⁹)(NR¹⁰R¹¹), —S(O)R¹² or        —SO₂R¹³;    -   R⁵ is H or substituted or unsubstituted substituted C₁₋₈alkyl;    -   R⁶ is —OC₁₋₈alkyl or OH;    -   R⁷ is H or substituted or unsubstituted C₁₋₈alkyl;    -   R⁸ is H or substituted or unsubstituted C₁₋₈alkyl;    -   R⁹ is H or substituted or unsubstituted C₁₋₈alkyl;    -   R¹⁰ is H or substituted or unsubstituted C₁₋₈alkyl;    -   R¹¹ is H or substituted or unsubstituted C₁₋₈alkyl;    -   R¹² is H, —OH, NR¹⁴R¹⁵ or substituted or unsubstituted        C₁₋₈alkyl;    -   R¹³ is H or substituted or unsubstituted C₁₋₈alkyl;    -   R¹⁴ is H or substituted or unsubstituted C₁₋₈alkyl; and    -   R¹⁵ is H or substituted or unsubstituted C₁₋₈alkyl;    -   or an enantiomer, diastereomer or tautomer thereof;    -   or a zwitterion or pharmaceutically acceptable salt of the        foregoing;    -   wherein:

each substituted C₁₋₈alkyl is independently substituted with one or morehalogen, hydroxyl, C₃₋₈cycloalkyl, amino, heterocyclyl, substituted orunsubstituted C₆-C₁₀aryl, carboxylic acid, phosphonic acid, phosphonate,phosphoric acid, sulphonic acid, sulfonamide, nitro, amide, ester, etheror ketone;

each substituted C₃₋₈cycloalkyl is independently substituted with one ormore halogen, hydroxyl, sulfonyl sulfoxide C₁₋₈alkyl, sulfonamide,nitro, cyano, —OC₁₋₈ alkyl, amide, ester, ether, —SH, —SO₁₋₈ alkyl,—C₁₋₈ alkyl, ketone, alkylamino, amino, C₆-C₁₀aryl or C₃₋₈ cycloalkyl;

each substituted C₆-C₁₀aryl is independently substituted with one ormore halogen, hydroxyl, sulfonyl C₁₋₈alkyl, sulfoxide C₁₋₈alkyl,sulfonamide, carboxylic acid, C₁₋₈ alkyl carboxylate (ester), amide,nitro, cyano, —OC₁₋₆ alkyl, —SH, —C₁₋₈ alkyl, ether, ketone, aldehyde,C₁₋₈alkylamino, amino, C₃₋₈cycloalkyl or C₆-C₁₀aryl; and

each substituted heterocycle is independently substituted with one ormore halogen, hydroxyl, sulfonyl, sulfoxide, sulfonamide, nitro, cyano,—SH, —SC₁₋₈ alkyl, —C₁₋₈alkyl, carboxylic acid, ketone, amide, ester,ether, C₁₋₈alkylamino, amino, C₆-C₁₀aryl or C₃₋₈cycloalkyl.

In embodiment (2), there is provided a compound of embodiment (1),wherein R¹ is substituted or unsubstituted C₆aryl.

In embodiment (3), there is provided a compound of embodiment (1) or(2), wherein R¹ is C₆aryl substituted with at least one halogen.

In embodiment (4), there is provided a compound of any one ofembodiments (1), (2) or (3), wherein R¹ is substituted phenyl.

In embodiment (5), there is provided a compound of any one ofembodiments (1) through (4), wherein R¹ is phenyl substituted with atleast one halogen.

In embodiment (6), there is provided a compound of any one ofembodiments (1) through (5), wherein R¹ is 4-bromo-phenyl.

In embodiment (7), there is provided a compound of any one ofembodiments (1) through (6), wherein R⁴ is —C(O)R⁶.

In embodiment (8), there is provided a compound of any one ofembodiments (1) through (7), wherein R⁶ is —OC₁₋₈alkyl.

In embodiment (9), there is provided a compound of any one ofembodiments (1) through (8), wherein R⁶ is —OEt.

In embodiment (10), there is provided a compound of any one ofembodiments (1) through (9), wherein R³ is —NR⁵.

In embodiment (11), there is provided a compound of any one ofembodiments (1) through (10), wherein R⁵ is H.

In embodiment (12), there is provided a compound of any one ofembodiments (1) through (11), wherein n is 2.

In embodiment (13), there is provided a compound of any one ofembodiments (1) through (12), wherein m is 2.

In embodiment (14), there is provided a compound of any one ofembodiments (1) through (13), wherein R² is selected from methyl, ethyl,n-propyl and isopropyl.

In embodiment (15), there is provided a compound of any one ofembodiments (1) through (14), wherein each C₁₋₈ alkyl is independentlyoptionally replaced with C₁₋₄alkyl.

In embodiment (16), there is provided a compound of embodiment (15),wherein each C₁₋₄alkyl is independently selected from methyl, ethyl,n-propyl, isopropyl, butyl, tert-butyl, isobutyl and sec-butyl.

In embodiment (17), there is provided a compound which is ethyl3-{[2-(1-{[(4-bromophenyl)carbamoyl]amino}-4-ethyl-2,5-dioxoimidazolidin-4-yl)ethyl]amino}propanoate.

In embodiment (18), there is provided a pharmaceutical compositioncomprising as active ingredient a therapeutically effective amount of acompound according to any one of embodiments (1) through (17), and apharmaceutically acceptable carrier.

In embodiment (19), there is provided a compound or pharmaceuticalcomposition according to any one of embodiments (1) through (18) for usein treating an inflammatory disease condition.

In embodiment (20), there is provided a compound or pharmaceuticalcomposition according to any one of embodiments (1) through (18) for usein treating an inflammatory disease or condition, wherein the disease orcondition is an ocular inflammatory disease or condition or a dermalinflammatory disease or condition.

In embodiment (21), there is provided method of treating an inflammatorydisease or condition in a subject in need thereof, the method comprisingadministering a therapeutically effective amount of a compound orpharmaceutical composition according to any one of embodiments (1)through (18) to the subject, thereby treating the condition.

In embodiment (22), there is provided the method of embodiment (21),wherein the disease or condition is an ocular inflammatory disease orcondition or a dermal inflammatory disease or condition.

Compound names were generated with ACDLabs version 12.5. Some of theintermediate and reagent names used in the examples were generated withsoftware such as Chem Bio Draw Ultra version 12.0 or Auto Nom 2000 fromMDL ISIS Draw 2.5 SP1.

In general, characterization of the compounds was performed according tothe following methods. NMR spectra were recorded on a 300 or 600 MHzVarian NMR spectrometer and acquired at room temperature. Chemicalshifts are given in ppm referenced either to internal TMS or to thesolvent signal. Optical rotations were recorded on Perkin ElmerPolarimeter 341, 589 nm at 20° C., Na/Hal lamp.

All the reagents, solvents, catalysts for which the synthesis is notdescribed are purchased from chemical vendors such as Sigma Aldrich,Fluka, Bio-Blocks, Combi-blocks, TCI, VWR, Lancaster, Oakwood, TransWorld Chemical, Alfa, Fisher, Maybridge, Frontier, Matrix, Ukrorgsynth,Toronto, Ryan Scientific, SiliCycle, Anaspec, Syn Chem, Chem-Impex,MIC-scientific, Ltd; however some known intermediates, were preparedaccording to published procedures.

Usually the compounds of the invention were purified by columnchromatography (Auto-column) on Teledyne-ISCO CombiFlash with a silicacolumn, unless noted otherwise.

The following abbreviations are used in the examples:

THF tetrahydrofuranCD₃OD deuterated methanolRT room temperatureCH₂Cl₂ dichloromethaneNH₄Cl ammonium chlorideEtOAc ethyl acetateKCN potassium cyanide(NH₄)₂CO₃ ammonium carbonateNaHSO₃ sodium hydrogen sulfiteEtOH ethanolCF₃CO₂H trifluoroacetic acidEt₃N triethylamineMeOH methanol

Example 1 Intermediate 1 tert-Butyl (3-oxopentyl)carbamate

To a cold (−78° C.) solution ofN-[(1,1-dimethylethoxy)carbonyl]-β-Alanine [CAS #3303-84-2] (2 g, 10.6mmol) in THF (50 mL) was added a solution of ethyl lithium incyclohexane (0.5 M solution, 64 mL, 32 mmol). The reaction was warmed to0° C. and stirred at 0° C. for 90 min. The reaction was quenched withaq. NH₄Cl, and extracted with EtOAc. The organic layer was washed withbrine, dried and the solvent removed under reduced pressure.Intermediate 1 was isolated as colorless oil.

¹HNMR (CD₃OD) δ: 1.05 (t, J=7.3 Hz, 3H), 1.40 (s, 9H), 2.42 (q, J=7.3Hz, 2H), 2.63 (t, J=5.7 Hz, 2H), 3.35 (q, J=5.6 Hz, 2H).

Example 2 Intermediate 2 tert-Butyl(2-(4-ethyl-2,5-dioxoimidazolidin-4-yl)ethyl)carbamate

A mixture of Intermediate 1 (350 mg, 1.74 mmol), KCN (230 mg, 3.48mmol), (NH₄)₂CO₃ (1.12 g, 12.2 mmol), NaHSO₃ (220 mg, 2.1 mmol) and EtOH(10 mL) was heated in a sealed tube for 18 h. The crude reaction wasfiltered through a celite column. The solvent was removed under reducedpressure, the crude product was purified by silicagel chromatographyusing EtOAc in hexane as eluent. Intermediate 2 was isolated as a whitesolid.

¹HNMR (CD₃OD) δ: 0.85 (t, J=7.3 Hz, 3H), 1.42 (br s, 9H), 1.60-1.82 (m,2H), 1.83-2.00 (m, 2H), 2.90-3.04 (m, 1H), 3.05-3.19 (m, 1H).

Example 3 Intermediate 3 tert-Butyl(2-(1-amino-4-ethyl-2,5-dioxoimidazolidin-4-yl)ethyl)carbamate

A solution of Intermediate 2 (132 mg, 0.46 mmol) and hydrazine hydrate(2 mL) was stirred at 120° C. in a sealed tube for 10 h. The reactionmixture was then diluted with water, extracted with EtOAc, the organiclayers were washed with brine, dried and the solvent was removed underreduced pressure. Intermediate 3 was isolated as a clear oil.

¹HNMR (CD₃OD) δ: 0.85 (t, J=7.3 Hz, 3H), 1.41 (s, 9H), 1.61-1.85 (m,2H), 1.91-2.04 (m, 2H), 2.85-3.03 (m, 1H), 3.04-3.17 (m, 1H).

Example 4 Intermediate 4 tert-Butyl(2-(1-(3-(4-bromophenyl)ureido)-4-ethyl-2,5-dioxoimidazolidin-4-yl)ethyl)carbamate

A solution of Intermediate 3 (64 mg, 0.23 mmol), 4-bromophenylisocyanate (50 mg, 0.25 mmol) in dioxane (5 mL) was stirred at RT for 1h. The solvent was removed under reduced pressure and the crude productwas purified by silicagel chromatography using EtOAc in hexane aseluent. Intermediate 4 was isolated as a white solid.

¹HNMR (CD₃OD) δ: 0.81-1.00 (m, 3H), 1.40 (br s, 9H), 1.64-1.92 (m, 3H),2.00-2.17 (m, 1H), 2.90-3.12 (m, 1H), 3.17-3.32 (m, 1H), 7.24-7.47 (m,4H).

Example 5 Intermediate 51-(4-(2-Aminoethyl)-4-ethyl-2,5-dioxoimidazolidin-1-yl)-3-(4-bromophenyl)urea

A solution of Intermediate 4 (60 mg, 0.12 mmol), CF₃CO₂H (1 mL) andCH₂Cl₂ (5 mL) was stirred at ambient temperature for 2 h. Solvent wasremoved under reduced pressure, the crude Intermediate 5 was used as itis in the next step.

Example 6 Compound 1 Ethyl3-{[2-(1-{[(4-Bromophenyl)carbamoyl]amino}-4-ethyl-2,5-dioxoimidazolidin-4-yl)ethyl]amino}propanoate

A mixture of crude intermediate 5 (47 mg, 0.12 mmol), ethyl acrylate (1mL, excess), Et₃N (1 mL) and EtOH (7 mL) was heated to 50° C. for 2days. The solvent was removed under reduced pressure, and the crudereaction mixture was purified by silicagel chromatography using MeOH inCH₂Cl₂. Compound 1 was isolated as thick yellow oil.

¹HNMR (CD₃OD) δ: 0.93 (t, J=7.3 Hz, 3H), 1.20 (t, J=6.9 Hz, 3H),1.62-1.81 (m, 2H), 2.09-2.24 (m, 1H), 2.35-2.51 (m, 1H), 2.60 (t, J=6.9Hz, 2H), 3.39-3.52 (m, 3H), 3.57-3.73 (m, 1H), 4.11 (q, J=6.9 Hz, 2H),7.40 (s, 4H).

Biological Data

Biological activity of compounds according to Formula I is set forth inTable 1 below. CHO-Gα16 cells stably expressing FPR2 were cultured inF12 media (10% FBS, 1% PSA, 400 μg/ml geneticin and 50 μg/mlhygromycin). In general, the day before the experiment, 18,000cells/well were plated in a 384-well clear bottom poly-D-lysine coatedplate. The following day the screening compound-induced calcium activitywas assayed on a FLIPR^(Tetra). The drug plates were prepared in384-well microplates using EP3 and MultiPROBE robotic liquid handlingsystems. Compounds were tested at concentrations ranging from 0.61 to10,000 nM. Results are expressed as EC₅₀ (nM) and % efficacy values.

TABLE 1 FPR2 Gα16- CHO EC₅₀ nM Compound Compound IUPAC name (% eff) 1Ethyl 3-{[2-(1-{[(4-Bromo- 49 phenyl)carbamoyl]amino}-4-ethyl-2,5-(0.97) dioxoimidazolidin-4-yl)ethyl]amino}propanoate

1. A compound represented by Formula I:

wherein: R¹ is optionally substituted C₁₋₈ alkyl, optionally substitutedC₃₋₈ cycloalkyl, optionally substituted C₆-C₁₀ aryl, or optionallysubstituted heterocycle; R² is H, or optionally substituted C₁₋₈alkyl;R³ is O or NR⁵; n is 1 or 2; m is 1 or 2; R⁴ is —C(O)R⁶,—P(O)(OR⁷)(OR⁸), —P(O)(OR⁹)(NR¹⁰R¹¹), —S(O)R¹² or —SO₂R¹³; R⁵ is H oroptionally substituted C₁₋₈alkyl; R⁶ is —OC₁₋₈alkyl or OH; R⁷ is H oroptionally substituted C₁₋₈alkyl; R⁸ is H or optionally substitutedC₁₋₈alkyl; R⁹ is H or optionally substituted C₁₋₈alkyl; R¹⁰ is H oroptionally substituted C₁₋₈alkyl; R¹¹ is H or optionally substitutedC₁₋₈alkyl; R¹² is H, —OH, NR¹⁴R¹⁵ or optionally substituted C₁₋₈alkyl;R¹³ is H or optionally substituted C₁₋₈alkyl; R¹⁴ is H or optionallysubstituted C₁₋₈alkyl; and R¹⁵ is H or optionally substituted C₁₋₈alkyl;or an enantiomer, diastereomer or tautomer thereof; or a zwitterion orpharmaceutically acceptable salt of the foregoing.
 2. The compoundaccording to claim 1, wherein R¹ is substituted C₆aryl.
 3. The compoundaccording to claim 1, wherein R¹ is substituted phenyl.
 4. The compoundaccording to claim 1, wherein n is
 2. 5. The compound according to claim1, wherein m is
 2. 6. The compound according to claim 1, wherein R³ isNR⁵, and R⁵ is H.
 7. The compound according to claim 1, wherein R⁴ is—C(O)R⁶, and R⁶ is —OC₁₋₈alkyl.
 8. The compound according to claim 1,wherein R² is selected from methyl, ethyl, n-propyl and isopropyl. 9.The compound according to claim 1, which is: Ethyl3-{[2-(1-{[(4-bromophenyl)carbamoyl]amino}-4-ethyl-2,5-dioxoimidazolidin-4-yl)ethyl]amino}propanoate.10. A pharmaceutical composition comprising as active ingredient atherapeutically effective amount of a compound according to claim 1, anda pharmaceutically acceptable carrier.
 11. A pharmaceutical compositionaccording to claim 10 wherein the compound is: Ethyl3-{[2-(1-{[(4-bromophenyl)carbamoyl]amino}-4-ethyl-2,5-dioxoimidazolidin-4-yl)ethyl]amino}propanoate.12. A method of treating a disease or condition associated with FPR2modulation in a subject in need thereof, the method comprisingadministering a therapeutically effective amount of a compound of claim1 to the subject.
 13. The method of claim 12, wherein the disease orcondition is an ocular disease or condition selected from dry eye,post-cataract surgical inflammation, and post-surgical corneal woundhealing or inflammation.
 14. The method of claim 12, wherein the diseaseor condition is a dermal disease or condition selected from psoriasis,rosacea and dermal wound healing.
 15. The method of claim 12, whereinthe disease or condition is pain.
 16. The method of claim 12, whereinthe disease or condition is selected from an immunological disorder,arthritis, rheumatoid arthritis and systemic lupus erythematosus. 17.The method of claim 12, wherein the disease or condition is inflammatorybowel disease.
 18. The method of claim 12, wherein the subject is ahuman.